The ability to image within diseased or sensitive tissue is highly desirable as it provides further information as to the underlying health of the tissue, but remains problematic in successful execution due to accessing the tissue without touching the surface. Significant problems with contact measurements (using a probe in contact with tissue) include the risk for infection of vulnerable tissues (e.g., wounds, burns, reconstructive tissue flaps) and the deformation of soft tissues (e.g., breasts) distorting blood flow and oxygenation.
Chronic wounds affect over 5 million Americans each year, resulting in over $20 billion in health care costs. Individuals with disabilities and diabetes as well as the elderly have the highest risk of developing chronic wounds. Patients afflicted with chronic wounds suffer from physical pain and disabilities in addition to psychological and emotional stresses and poor quality of life. Current treatments for chronic wounds include cleansing, debridement, maintaining a moist tissue environment, and when possible, eliminating the underlying pathology or factors that contributed to poor wound healing. In advanced cases, amputation may become necessary. Death, especially in elderly patients, may result from sepsis that can be associated with chronic wounds. Multiple factors can lead to impaired wound healing. Local factors that influence healing include tissue blood flow and oxygenation. Pressure ulceration, For example, occurs when the skin and underlying tissues are compressed for a period of time between the bone and the surface on which the patient is sitting or lying. Constant pressure against the tissue reduces blood supply to that area which results in tissue ischemia1, 2. Ultrasound imaging results have recently shown that early pressure ulcers originate from deep tissues attached to the bone and spread upwards, eventually to the skin3. Therefore, quantification of blood flow in deep wound tissues is crucial for accurate diagnosis and treatment monitoring.
As another example of tissue injury, a burn is damage to body's tissues caused by heat, chemicals, electricity, sunlight or radiation. Burns can cause swelling, blistering, scarring and, in serious cases, shock and even death. They also can lead to infections because they damage skin's protective barrier. Treatment for burns depends on the cause of the burn, how deep it is, and how much of the body it covers. Antibiotic creams can prevent or treat infections. For more serious burns, treatment may be needed to clean the wound, replace the skin, and make sure the patient has enough fluids, nutrition, blood flow, and tissue oxygen.
As a further example, mastectomy skin flap necrosis may ultimately lead to implant exposure, infection and implant loss. In some of these cases, the complications may be so devastating as to cause a failure of reconstruction4,5,6. Of the 75,000 expander-implant based reconstructions performed in 2013, more than 18,000 resulted in implant loss, secondary to complications7. The cost of implant loss alone is >$30,0008, plus the fees incurred by additional operating room time, clinic visits, inpatient stays, surgeon costs and procedure fees.
Similarly, head and neck cancer accounts for 3 to 5% of all cancers in the United States9. Despite all the advances in non-surgical treatments, surgery remains an important tool in the management of these cancers. Primary or salvage surgeries are extensive and often lead to major head and neck defects that require complex reconstructions with local flaps, regional flaps, or free tissue transfer flaps. Intraoperative decreases in blood flow after flap anastomosis have been observed10,11, which may lead to failure of flap thrombosis.
Thus, knowledge of tissue blood flow changes after tissue transfer may enable surgeons to predict the failure of flap thrombosis at an early stage to salvage ischemic flaps.
Current imaging diagnostic tools include x-ray computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) and ultrasonography, but most of these imaging methods are prohibitively expensive and generally only provide tissue morphological information. Moreover, some of these techniques (e.g., CT and PET) expose patients to ionizing radiation12,13. Doppler ultrasound is limited in measuring only blood flow in large vessels.
Often, the surface of a tissue does not provide sufficient feedback as to the health of the tissue within. For example, when flap ischemia is a concern, most surgeons rely primarily on careful and frequent visual examination of the flap surface. Several tools and techniques are currently in use to monitor flaps in order to detect changes in viability in a time frame that allows for salvage of the flap from its nonviable state. While transcutaneous or implantable ultrasound Doppler technologies are commonly used to assess blood flow through large axial vessels, peripheral flap blood flow remains largely subjective in its clinical assessment11,27-29. Laser Doppler technique has also been used to monitor blood flow at a tiny spot of superficial tissue, which may not reflect precisely hemodynamic changes in the bulk flap tissue10,30,31. The ischemia and hypo-perfusion that can occur intra-operatively in the flap are often not evident to the surgeons until days/weeks later when it presents as skin flap necrosis. Therefore, clinical assessment alone is not reliable. For example, mastectomy skin flap necrosis, infection and implant loss are all interlinked by a shortfall of perfusion and tissue oxygen at the microcirculatory level. Previously, a prospective clinical trial of tissue expander-implant breast reconstruction has been conducted with intraoperative evaluation of mastectomy skin flaps by clinical assessment, laser-assisted indocyanine green dye angiography, and fluorescein dye angiography32. Due to the requirement of an intravenous injection, these methods lack feasibility for continuous use in clinical preoperative and postoperative settings; and they are time-dependent, requiring evaluation after a particular time period following dye injection. Thus, noninvasive, continuous, and quantitative imaging methods are highly advantageous to assess tissue hemodynamic states and alterations for perioperative management flap ischemia to reduce the likelihood of postoperative ischemic complications.
Near-infrared (NIR: 650 nm to 900 nm) diffuse optical technologies provide a noninvasive and relatively inexpensive tool for functional imaging of tissue hemodynamics in deep microvasculature up to several centimeters14-17. The most commonly used NIR diffuse optical spectroscopy/tomography (DOS/DOT) can currently quantify tissue hemoglobin concentration and blood oxygen saturation. Traditional DOS/DOT using the fiber-optic interface has been used over several decades to detect distribution of oxygenation alternations in tissues18-22.
A relatively new NIR diffuse correlation spectroscopy (DCS) technique has been also developed for direct measurement of blood flow in deep tissues (up to ˜1.5 cm)23,24. DCS employs coherent NIR light to probe deep tissues and single-photon-counting avalanche photodiodes (APDs) to detect temporal speckle fluctuations of the diffuse light on tissue boundaries. Long-coherence lasers and APD detectors are connected with optical fibers placed on the tissue boundary for DCS measurements. The measured temporal speckle fluctuation depends on the motion of moving scatterers (primarily red blood cells in the microvasculature), which is related to a blood flow index (BFI). BFI can be quantified by iteratively fitting the measured light intensity autocorrelation function.
Despite advances in DCS technologies, there have been limited imaging applications of diffuse correlation tomography (DCT). A probe-tissue contact based DCS/DCT approach has been described, but as with other approaches it remains disadvantaged in vivo due in part to compression-induced hemodynamic alterations or potential infections on ulcerous tissues. Another limitation lies in their reliance on analytical solutions that assumed a simple semi-infinite flat tissue geometry. Thus, an approach without the request of contact measurement may address these limitations.